Aminoethanesulfonyl derivatives and their production

ABSTRACT

AMINOETHANESULFONYL DERIVATIVES HAVING A GENERAL FORMULA R-SO2CH2CH2Y WHERE R IS SELECTED FROM A GROUP CONSISTING OF THIAZOLYL-2-AMINO, 1-PYRROLYL, 4-METHYLPIPERAZYL, AND 1-INDOLYL AND Y IS NH2 OR, WHEN R IS THIAZOLYL2-AMINO, SAID Y MAY BE NICOTINOYLAMINO AS WELL AS MANUFACTURE METHODS THEREOF WERE DISCLOSED.

3,828,070 AMINOETHANESULFONYL DERIVATIVES AND THEIR PRODUCTION Shun-ichi Naito, 35 Murasakina Kamitoridacho, Kita-ku, Kyoto, Japan No Drawing. Original application July 19, 1971, Ser. No. 164,007, now Patent No. 3,743,647. Divided and this application Dec. 26, 1972, Ser. No. 318,555

Claims priority, application Japan, Aug. 27, 1970, 45/75,350, 45/75,351, 45/75,352; Dec. 18, 1970, 45/114,446, 45/114,447

Int. Cl. C07d 27/56 US. Cl. 260-32612 R 2 Claims ABSTRACT OF THE DISCLOSURE Aminoethanesulfonyl derivatives having a general formula RAO CH CH Y where R is selected from a group consisting of thiazolyl-Z-amino, l-pyrrolyl, 4-methylpiperazyl, and l-indolyl and Y is NH or, when R is thiazolyl- 2-amino, said Y may be nicotinoylamino as well as manufacture methods thereof were disclosed.

The present invention relates to aminoethanesulfonyl derivatives of the general formula in which R is selected from a group consisting of NH- i (t hlazoly1-2-amino) N I N- (1-pyrroly1),

CH3N N- (4-methylpiperazyl) and (1-indolyl) and Y is NH In case R is thiazolyl-Z-amino, the Y may also be nicotinoylamino. This invention also relates to manufacturing methods for these aminoethanesulfonyl derivatives.

This is a division of application Ser. No. 164,007, filed July 19, 1971 now U.S. Pat. No. 3,743,647.

-All of these aminoethanesulfonyl derivatives are novel compounds having never been disclosed in any literature including patent specification. They are useful as medicines, such asanalgesics, with little side effects. These compounds are characterized by containing taurine which is one of amino acids and has surface activity as well as analgesic action and, when they are given to human beings, their effects are not lowered even when subjected to a detoxication reaction in viva such as an acetylation. Furthermore, some of these compounds are also useful as anti-histaminic, hypocholesterolemic and anti-inflammatory drugs.

Although the compounds of this invention have considerable water solubility, they are resistant to moisture to such an extent that, even when they are allowed to stand in an open container placed in a room for one year, more than 90% of the content remains unchanged in most cases indicating little absorption of moisture. In

nited States Patent Oifice 3,828,070- Patented Aug. 6, 1974 addition, the aqueous solution thereof is also stable. Thus, for example, when a 5% aqueous solution of them is allowed to stand at room temperature for one year, more than -95% thereof remains unchanged. This is practically advantageous, particularly in view of use of the compounds in injection.

Compounds of this invention can be manufactured by various routes which will be explained in detail.

Thus, for example, compounds where Y is nicotinoylamino group can be manufactured by nicotinoylation of the corresponding amino compounds or by nicotinoylamination of the corresponding halides. The latter method (nicotinoylamination of halides) will be disclosed later in an item of amination reaction.

The former method, i.e. nicotinoylation of aminoethanesulfonylaminothiazole (I), may be represented as:

In order to carry out the present nicotinoylation, any of known method for nicotinoylation may be employed. It is preferred to effect the nicotinolylation by use of acids bearing a nicotinoyl group or the functional derivatives thereof such as acid anhydrides, acid esters, acid halides or the mixtures thereof. These acids and their functional derivatives may also be employed in the form of their salts. The reaction may be carried out at either normal temperature or with heating and under normal pressures or pressures above normal, depending upon the kinds, quantities or the like of the reactants used. Furthermore the starting material (I) of the present reaction may be employed in its salt form.

The present method will be further explained in detail with particular reference to the following examples, but it will be understood that these examples be preferred embodiments of the present method used only to illustrate but not limit the invention.

Example 1 Into 0.1 mole of the starting material or its hydrochloride is added from to 2-00 ml. of anhydrous pyridine with subsequent addition of nicotinic acid chloride hydrochloride (0.1 mole). After heating the mixture for an hour, or, alternatively, standing the same whole day at a room temperature, the mixture is heated for an additional one hour. The pyridine is distilled off under reduced pressure from the reaction mixture, the residue recrystallized several times from either methanol or from ethanol to obtain the desired product (II) as its hydrw chloride having a melting point of 289 C. (colorless needles). Into said residue from which the pyridine has been distilled off is added water and the mixture is made alkaline (pH about 9) by use of aqueous ammonia (of about 28%). The resulting mixture is evaporated under reduced pressure to dryness and the residue recrystallized several times from water to obtain the desired product (II) as colorless needles having a melting point of 228 C. The yields of the desired product and its hydrochloride are almost identical and within the range of from about 70 to 75% of the theory.

3 Element Analysis Desired product (II) Calculated for C H N O S C 42.31; H 3.85; N

17.95 Found: C 42.37; H 3.90; N 18.03 The hydrochloride of the desired product (II) Calculated for C H N O S Cl C 34.29; H 3.64;

N 14.55 Found: C 34.40; H 3.51; N 14.58

Employment of nicotinic acid chloride in place of the nicotinic acid chloride hydrochloride did not cause any change in yields. Furthermore, it has been ascertained that the condensation reaction between the starting material (II) or the salt therof, and nicotinic acid chloride can proceed also in water or various organic solvents,

I as well as in pyridine and that it also proceeds advantageously when a small quantity of pyridine of alkali is added into the water or various organic solvents.

For example, 0.1 mole of the starting material (I) or its hydrochloride is charged with 500 ml. of ethyl acetate, into which mixture 0.1 mole of nicotinic acid chloride hydrochloride is added followed by heating under reflux in water bath for 3 hours. After distilling OK the ethyl acetate from the reaction mixture remain yellowish solids, which are then recrystallized from ethanol or methanol to obtain the hydrochloride of the desired product (II). Alternatively, said residual solids are dissolved in a small amount of water, which solution is made alkaline by use of ammonia (pl-I about 9) and distilled under reduced pressure to remove the water. The residue is recrystallized from water to obtain the desire product (II) in its pure form. In this case, the yield was little different from that obtained in the case of employment of pyridine as solvent.

In addition, in the following examples '2 and 3 are shown the embodiments of the invention wherein nicotinic acid anhydride and nicotinic acid are employed in place of nicotinic acid chloride (hydrochloride) used in Example 1.

Example 2 Into a 100 ml. three-necked flask are placed (Ll mole of the starting material (I), 0.1 mole of nicotinic acid anhydride and 100 ml of anhydrous pyridine followed by heating the mixture on boiling water bath with agitation for 7 hours. The pyridine is distilled off under reduced pressure and to the residue is added strong aqueous ammonia (of about 28%) to make it alkaline, whereupon yellowish-white substance precipitates. The mixture is, as such, subjected to distillation under reduced pressure to remove the water, the residue recrystallized several times from water to obtain the desired product (II) in its pure form. The crystals, when subjected to mixed examination using the corresponding standard, show no lowering in Into a three-necked flask with a water-separating tube attached thereto are charged 0.1 mole of the starting material (I), 0.1 mole of nicotinic acid and 400 ml. of pcymene followed by heating with stirring at a temperature of from 180 to 190 C. for about 6 hours. The water formed is azeotropically distilled off. After cooling, the p-cymene is distilled olf under reduced pressure, the residue being made alkaline (pH about 9) by use of strong aqueous ammonia followed by distilling off the water under reduced pressure. The residue is recrystallized several times from water to obtain the pure desired product (II). The product, when subjected to mixed examination using the corresponding standard material, show no lowering in its melting point. The yield is about 65%.

Referring now by way of precaution, the method according to the present invention can also be effected by proceeding the reaction in the presence of catalyst. Nicotinoylaminoethanesulfonylaminothiazole (II) contains, in its structure, a pyridine ring of nicotinic acid and, since the nitrogen atom in said ring is basic, it may be, of course, optionally reacted with any organic or inorganic acid to form the corresponding acid addition salt. Subsequently, in order to purify the end product, there may be employed, as well as the hydrochloride, any organic salts as for example, its fumarate, flavinate or tartarate. For example, the end product (II) may be readily purified by forming its hydrochloride by either adding thereto concentrated hydrochloric acid followed by evaporation under reduced pressure to dryness or introducing gaseous HCl into a solution of the desired product (II) in methanol or ethanol, with subsequent recrystallization of the hydrochloride from methanol or ethanol.

The above disclosure is an explanation in detail of a method to manufacture nicotinoylamino compounds by nicotinoylation of the corresponding amino compounds.

Compounds of the present invention in which Y is an amino radical can be manufactured by the following two methods:

( l) Amination of the corresponding halides (2) Deacylation of the corresponding acylamino (or acylimino) compounds The amination according to (1) will be explained at first together with a nicotinoylamination of the corresponding halides for the sake of convenience.

Said amination method can be accomplished by the reaction of the halide of the formula R4o,cH cH,z (III) (where R is as defined already; Z is halogen) with ammonia or nicotinic acid amide.

The halogen designated by Z in the above-described formula is preferably chlorine, bromine or iodine, of which chlorine is particularly preferred.

The ammonia or nicotinic acid amide to be reacted may be used as such or after dissolving or suspending in water and/or organic solvent, and its salts with acids may also be employed, if desired. The reaction in accordance with the present invention may proceed under normal pressure, although it is preferred to carry out the reaction under pressure above normal, in which case it is more preferred to effect the reaction in the presence of catalyst as for example, NaI, Cu Cl NHJ or the like compound.

The halides to be employed as the starting materials according to the present invention are also novel compounds having been described in no literature and may be prepared, for example, by reacting Z-aminothiazole, N-methylpiperazine, pyrrole or indole with haloethylsulfonyl halide.

The present invention will be further described in detail with particular reference to the following examples, but it will be understood that these examples be preferred embodiments of the present invention and the invention he never limited thereto.

Example 4 (Y=NH 10 G. of the compound of the formula (III) wherein X is C] is reacted in an autoclave in the presence of catalyst with either anhydrous ammonia or with ammonium carbonate and aqueous ammonia by heating the reactants. After completion of the reaction, the contents are made acidic by use of hydrochloric acid, the resulting precipitates removed by filtering off the same under suction, the filtrate evaporated under reduced pressure to dryness and the residue recrystallized from quantities of ethanol to obtain the hydrochloride of the desired product. Alternatively, the said filtrate is made alkaline by use of strong aqueous ammonia (to pH about 9) followed by evaporation under reduced pressure to dryness, the residue recrystallized from either water or from a mixture of water and acetone to obtain the desired product. The melting points and details of the reaction conditions are shown in Table 2, while the element analysis in Table 3.

TABLE 1 M.P. of the desired MP. of the hydrochloride of the The above is an explanation as to the manufacture of the desired compounds by amination (and nicotinoylamination) of the corresponding halides.

R p u desired product As hereunder is an explanation of deacylation of the M.P. 345-352 (colored M.P. 318-319" (colored 5 corresponding acylamino acylimmo) compounds- CHi-N N sa d p dk e More particularly, said method is concerned with a proc- 0 or e85 crys a 0 or 958 crys a ess for preparing the desired products by deacylating, by (Ia) way of hydrolysis or hydrazinolysis, a compound repre- M.P. 352356 (colored M.P. sin-322 (colored Sented by the general formula V N- and decomposed) and decomposed) 10 Colorless crystals. Colorless crystals. 2 2 2Q (H) N M P.325 332.(c01ored MP. zlfiucolofless wherein R represents the same meanings as described I and decomposed) crystals. above and Q is an acylamino or acylimino group. Pre L odorless crystals' ferred examples of the acylamino group include aliphatic s acylamino groups such as acetylamino and propionyla- (Id) mino groups, as Well as aromatic amino groups such as 2 o 1 d MP 258 2640 l d benzoylamino and nicotinoylamino groups. Preferred ex- ;,E.- fii;,, g;,g g g ggfl ample of the acylimino group is phthalimino group. Of course, these specific examples of the acylamino and acylimino groups are mentioned only by way of example to N explain the present invention. Therefore it will be under- I stood that the present invention be by no means restricted (Te) to employment of such specific examples.

TABLE 2 Catalyst and Yield (percent) the added Reaction Tcm eraamount Starting amine (G.) time (hrs.) ture( C.) Ia Ib Id Ie thereof (g.)

5 100 50 43 36 40 Nal 0.45) f ul fi fi fi iql. 5 100 52 45 40 43 0112012 (1.0) ii ir iibi 28% NHQH s 140 as 34 3s Cl12Cl2 (0.4

No The above-described hydrolysis may be elfected advan- When the above-described reaction was repeated except Eageously any known manner where there employed or example, acids, sodium alcoholate, alkali metal hythat there was employed, as the starting material, the brod roxides, alkali metal carbonates or the like materials. In mide (X=Br) or iodide (X=I) in place of the chloride particular, preferred results may be obtained in the pres- (X==Cl) there resulted some reduction in yields. Similar ed in ields Occurrred also when using no catalysts ent invention when a concentrated solution of alkali metal I y 4O hydroxide such as NaOH or KOH.

EXample 5 (Y=Nlcotlnoylamlno) When the deacylation of the invention is to be elfecte d To 5 g. of the compound of the formula (II) wherein by hydrazln9lyslsi there y fi y fi y knowfl R is thiazolyl and Z is added 3 g. of nicotinic acid amide memos! for It, Such one whereirg hydrazine hydrate is or its hydrochloride, and the mixture is reacted, in a added into a methanolic or ethanolic solution with subseautoclave, in the presence of 3 g. of Cu Cl at a tempera- 45 quent {Teatment Y y f acldture of 100 C. for about 6 hours. The contents are there Startlng {nateflals 1n thlS Cl fir also n vel 60mafter made acidic by use of hydrochloric acid, the precipipounds having never been described in any literature and tates formed thereby filtered off under suction. The filtrate y p p f a p y theft-336151011 of is evaporated under reduced pressure to dryness, the resi- Y P PQ i PY iIld le 0r 2-aminothiazole with due recrystallized from methanol or ethanol to obtain the an acylamlnoethanesulfollyl halldehydrochloride of the desired product (i.e. nicotinoylami- Pfesnt method W111 be h r Illustrated in detail noethanesulfonylaminothiazole hydrochloride). w th particular reference to the following examples, but it Alternatively, the filtrate as described above is made will be understood that these examples be preferred emalkaline by use of ammonia and evaporated under rebodiments of the present method and the present invention duced pressure to dryness, the residue being recrystallized be never limited thereto. from water to obtain the desired product as colorless nec- Exa mp1 5 6 dles. Yield about 20%. alts molecular weight and element l i are Shown i T bl 3 A i E l 4, there Into the starting material wherein Q is phthalimino resulted some reduction in yield when there was employed, group 18 added 0 Y P r t Solution of hydroxide as the starting material, the bromide (Z=Br) o iodid followed by boiling the mixture under reflux for 31-5 hours. (2:1) or no catalyst were employed. After cooling the mixture is made acidic by use of concen- The desired product wherein R is thiazolyl-Z-amino and trated hydrochloric acid while ice-cooling, and then ad- Y is nicotinoylamino) has a melting point of 229 C. and usted to a pH of about 9 by addition of sodium carbonate. the hydrochloride thereof of 288 C. The crystals precipitated thereby are separately stored.

TABLE 3 Calculated (percent) Found (percent) Molecular Compound formulas C H N C H N Ia. (N-methylpiperazine family). C7 17 302s 40. 58 8.21 20.29 40. 8.18 20.20 In (hydrochloride)- C7H20N302SC12 26.50 6.31 13.25 26.72 6.28 13.33 CaH1oN302S 41.38 5. 74 16.09 41.25 5.82 16.21 16 (hydr0chloride) CiHiiNiOiSCi, 29.15 4.37 11.34 29.28 4.76 11.42 10 ciiHirNioisr 42.31 3.85 17.95 42.38 3.91 17.72 10 (hydrochloride) CllHl|N40$s2Gh 34.29 3.64 14.55 34.31 3.60 14.47 1 .HeNeOrSr 28. 99 4.35 20.29 29.12 4.21 20. 34 CrHi Nro s ch 21.43 3.93 15.00 21.38 3.99 15.23 C10 12 2 53.57 5.36 12.50 53.63 5.28 12.63 CioHnNrOzSCl 46. 07 4.99 10.75 46.11 4. s9 10. 3s

The filtrate is evaporated under reduced pressure to dry- 8 All of the resulting products are in the form of colorless crystals.

ness, the residue being recrystallized from either Water or TABLE Amount from a mixture of water and acetone and the result ng R Q usedog.) Yield crystals, together with the previously stored crystals, being Phthafimmo 4 5 recrystallized several times from either water or from a CHa-N /N Acct-amino 10 4.7 mixture of water and acetone to obtain the desired prod- Phthamnim 10 M not as colorless crystals. The details of these reactions are I N- Acetammo 10 .4. 3

10 J shown 1n Table 4. Phthallmino 10 5.0 Similar procedures are repeated except that there are Aceramino 10 ,2 employed, as the starting material, ones wherein Q is benzoylamino or acetylamino group, the corresponding desired products are obtained in yields as tabulated in l 1 d d h -N Phthalimino 1o 3. Table 5. The element ana ysis of the desire pro ucts t us l Acetamim 10 5 obtained are shown in Table 6.

TABLE 6 Calculated (percent) Found (percent) R Molecular formula C H N C H N C H1 N O2S 40.58 s. 21 20. 29 40.67 8.18 20. 33 HaC-N N- i CdHIONZO'ZS 41.33 5. 74 16.00 41. 5.33 16.22

O1oHi2N2O2S 53. 57 5. 12.50 53.68 5. 3s 12. 60

CSHQNZOZSZ 28.99 4.35 20.29 29.05 e30 20.38

TABLE 4 (colored and decomposed).

(colored and decomposed).

(colored and decomposed).

R (10 g.) d) g- \T 40 Ml. 325-332 (colored and decomposed) No'rE.-All oi the resulting products are in the form of colorless erystals.

Example 6 To the starting material wherein Q is phthalimino group is added from about 5 to 8 times its volume of ethanol followed by the addition of 1.1 times its molar amount of hydrazine hydrate (of about The mixture is heated under reflux for about 2 hours with continuous stirring. Thereafter, the mixture is adjusted to a pH of about 1 by the addition of hydrochloric acid, heated on water bath for further about 30 minutes and filtered in hot to remove the precipitated phthalic acid hydrazide, the filtrate being cooled to precipitate the hydrochloride of the desired product which is then filtered and then recrystallized several times to purify the same. [Alternatively, the said filtrate is evaporated under reduced pressure to dryness and the residue is made alkaline (pH about 9) by the addition of a Na CO solution followed by evaporating again under reduced pressure to drynes. The residue is recrystallized several times from water or from a mixture of water and acetone to obtain the free desired product.] The details of the reactions are shown in Table 7. In addition, the element analysis of the hydrochloride of the desired product is shown in Table 8.

9 10 By the way, when, in Example 6, sodium carbonate is 2. The compound according to claim 1 which has the employed to make the reaction mixture alkaline, the hyformula:

drochloride as obtained in this example may be also obtained by reducing the amount thereof added and thereby making the mixture weakly acidic. 5 NSO CH CHgNH TABLE 7 Amount of Solvent The used for starting Hydrazine M.P. of the recrystalmaterial hydrate H01 salt of the Yield lizing the R used (g.) (g.) desired product (g.) HCl salt 130 22 M.P. 3183l9 52 Ethanol. CH N N (colored and decomposed).

\ 122 22 M.P. 319322 45 D0. H- (colored and decomposed).

M.P. 258-264 Do. (colored and U decomposed).

M.P. 325-332 Methanol. --N (colored and i I decomposed). S NH TABLE 8 Calculated (percent) Found (percent) R Molecular formula C H N C H N C7H2oN3O2S Cl 26. 50 6. 31 13. 25 26. 43 6. 45 13. 38 OHa-N N- \N CcHxzNzOzSCl 29. 15 4. 87 11. 34 29. 27 4. 78 11. 45 a Q ('hgHgNzOzSCl 46. 07 4. 99 10. 75 46. 11 4. 87 10. 82

NJ I

I claim: 45 1. A compound of the formula: References Cited UNITED STATES PATENTS 3,472,870 10/ 1969 Larsen et a1. 260-32612 R 0 5 JOSEPH A. NARCAVAGE, Primary Examiner and the pharmaceutically acceptable acid addition salts thereof. 

